Novel mutations identified in Chinese families with autosomal dominant congenital cataracts by targeted next-generation sequencing.
Li Shan,Zhang Jianfei,Cao Yixuan,You Yi,Zhao Xiuli
BMC medical genetics
BACKGROUND:Congenital cataract is a clinically and genetically heterogeneous visual impairment. The aim of this study was to identify causative mutations in five unrelated Chinese families diagnosed with congenital cataracts. METHODS:Detailed family history and clinical data were collected, and ophthalmological examinations were performed using slit-lamp photography. Genomic DNA was extracted from peripheral blood of all available members. Thirty-eight genes associated with cataract were captured and sequenced in 5 typical nonsyndromic congenital cataract probands by targeted next-generation sequencing (NGS), and the results were confirmed by Sanger sequencing. Bioinformatics analysis was performed to predict the functional effect of mutant genes. RESULTS:Results from the DNA sequencing revealed five potential causative mutations: c.154 T > C(p.F52 L) in GJA8 of Family 1, c.1152_1153insG(p.S385Efs*83) in GJA3 of Family 2, c.1804 G > C(p.G602R) in BFSP1 of Family 3, c.1532C > T(p.T511 M) in EPHA2 of Family 4 and c.356G > A(p.R119H) in HSF4 of Family 5. These mutations co-segregated with all affected individuals in the families and were not found in unaffected family members nor in 50 controls. Bioinformatics analysis from several prediction tools supported the possible pathogenicity of these mutations. CONCLUSIONS:In this study, we identified five novel mutations (c.154 T > C in GJA8, c.1152_1153insG in GJA3, c.1804G > C in BFSP1, c.1532C > T in EPHA2, c.356G > A in HSF4) in five Chinese families with hereditary cataracts, respectively. NGS can be used as an effective tool for molecular diagnosis of genetically heterogeneous disorders such as congenital cataract, and the results can provide more effective clinical diagnosis and genetic counseling for the five families.
10.1186/s12881-019-0933-5
GJA8 missense mutation disrupts hemichannels and induces cell apoptosis in human lens epithelial cells.
Li Li,Fan Da-Bei,Zhao Ya-Ting,Li Yun,Yang Zi-Bing,Zheng Guang-Ying
Scientific reports
Autosomal dominant congenital cataract (ADCC), the most common hereditary disease, is a major cause of eye disease in children. Due to its high genetic and clinical heterogeneity, the identification of ADCC-associated gene mutations is essential for the development of molecular therapies. In this study, we examined a four-generation Chinese pedigree with ADCC and identified putative mutations in ADCC candidate genes via next-generation sequencing (NGS) followed by Sanger sequencing. A novel missense mutation in GJA8 (c.T217C) in ADCC patients causes a serine-to-proline substitution at residue 73 of connexin 50 (Cx50); no mutation was found in unaffected family members and unrelated healthy individuals. Functional analysis revealed that this missense mutation disrupts protein function in human lens epithelial cells (HLEpiCs), which fails to form calcium-sensitive hemichannels. Furthermore, mutant Cx50 leads to decreased ROS scavenging by inhibiting G6PD expression and thus induces cell apoptosis via aberrant activation of the unfolded protein response (UPR). In conclusion, we report a novel GJA8 heterozygous mutation in a Chinese family with a vital role in ADCC, broadening the genetic spectrum of this disease.
10.1038/s41598-019-55549-1
The mutation spectrum in familial versus sporadic congenital cataract based on next-generation sequencing.
Fan Fan,Luo Yi,Wu Jihong,Gao Chao,Liu Xin,Mei Hengjun,Zhou Xiyue
BMC ophthalmology
BACKGROUND:Congenital cataract (CC) is a significant cause of lifelong visual loss, and its genetic diagnosis is challenging due to marked genetic heterogeneity. The purpose of this article is to report the genetic findings in sporadic and familial CC patients. METHODS:Patients (n = 53) who were clinically diagnosed with CC and their parents were recruited. Blood samples were collected in our hospital. Mutations were detected by panel-based next-generation DNA sequencing (NGS) targeting 792 genes frequently involved in common inherited eye diseases. RESULTS:We identified variants in 10/37 cases (27.02%) of sporadic CC and 14/16 cases (87.5%) of familial CC, which indicated a significant difference (P = 0.000). Of the 13 variants identified in sporadic cases, nine were previously reported mutations, and three were novel mutations, including one de novo mutation (CRYBB2 c.487C > T). The most frequent variants in our cohort were in crystallins and cytoskeletal genes (5/27, 18.52%), followed by proteins associated with X-linked syndromic conditions (14.81%) and transcriptional factors (11.11%). Additional information on the possibility of complications with inherited ocular or systemic diseases other than CC was provided in 17/27 (62.96%) variants. CONCLUSIONS:These results contribute to expanding the mutation spectrum and frequency of genes responsible for CC. Targeted NGS in CC provided significant diagnostic information and enabled more accurate genetic counselling. This study reports the different distributions of mutation genes in familial and sporadic CC cases.
10.1186/s12886-020-01567-x
Recent developments in the management of congenital cataract.
Bremond-Gignac Dominique,Daruich Alejandra,Robert Matthieu P,Valleix Sophie
Annals of translational medicine
Congenital cataract is a rare eye disease, one of the leading treatable causes of low vision in children worldwide. Hereditary cataracts can be divided in syndromic and non-syndromic cataracts. Early diagnosis in congenital cataracts is key to reach good visual function. Current surgical techniques, that combine microincision cataract extraction and primary intraocular lens (IOL) implantation, have improved childhood cataract outcome. Complications include posterior capsule opacification (PCO), aphakic or pseudophakic glaucoma, uveitis, pupil displacement and IOL decentration. A recent study using a modified Delphi approach identified areas of consensus and disagreement in the management of pediatric cataract. A consensus or near consensus was achieved for 79% of the questions, however 21% of the questions remained controversial, as for IOL implantation strategy. Congenital cataracts show a highly variable phenotype and genotype, and can be related to different mutations, genetic variance, and other risk factors. Congenital cataracts can be associated with other ocular developmental abnormalities, including microphthalmia, microcornea, or aniridia and with systemic findings. Next-generation sequencing (NGS) and forthcoming new ultra-high-throughput sequencing represent excellent tools to investigate the genetic causes of congenital cataracts. A better recognition of different clinical presentations and underlying etiologies of congenital cataracts may lead to the development of new approaches to improve visual outcome after cataract surgery and promote early detection of systemic associated syndromes.
10.21037/atm-20-3033
Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families.
International journal of molecular sciences
EPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic variants associated with congenital cataracts, variable microcornea, and lenticonus, but no previous association with microphthalmia (small, underdeveloped eye, ≥2 standard deviations below normal axial length). Microphthalmia arises from ocular maldevelopment with >90 monogenic causes, and can include a complex ocular phenotype. In this paper, we report two pathogenic variants in unrelated families presenting with bilateral microphthalmia and congenital cataracts. Whole genome sequencing through the 100,000 Genomes Project and cataract-related targeted gene panel testing identified autosomal dominant heterozygous mutations segregating with the disease: (i) missense c.1751C>T, p.(Pro584Leu) and (ii) splice site c.2826-9G>A. To functionally validate pathogenicity, morpholino knockdown of / in zebrafish resulted in significantly reduced eye size ± cataract formation. Misexpression of N-cadherin and retained fibre cell nuclei were observed in the developing lens of the knockdown morphant fish by 3 days post-fertilisation, which indicated a putative mechanism for microphthalmia pathogenesis through disruption of cadherin-mediated adherens junctions, preventing lens maturation and the critical signals stimulating eye growth. This study demonstrates a novel association of with microphthalmia, suggesting further analysis of pathogenic variants in unsolved microphthalmia cohorts may increase molecular diagnostic rates.
10.3390/ijms22042190
Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families.
Genes
Our purpose was to identify mutations responsible for non-syndromic congenital cataracts through the implementation of next-generation sequencing (NGS) in our center. A sample of peripheral blood was obtained from probands and willing family members and genomic DNA was extracted from leukocytes. DNA was analyzed implementing a panel (OFTv2.1) including 39 known congenital cataracts disease genes. 62 probands from 51 families were recruited. Pathogenic or likely pathogenic variants were identified in 32 patients and 25 families; in 16 families (64%) these were de novo mutations. The mutation detection rate was 49%. Almost all reported mutations were autosomal dominant. Mutations in crystallin genes were found in 30% of the probands. Mutations in membrane proteins were detected in seven families (two in and five in ). Mutations in and were each found in three families. Other mutations detected affected and . Variants classified as of unknown significance were found in 5 families (9.8%), affecting and . Mutations lead to different cataract phenotypes within the same family.
10.3390/genes12040580